Abstract：
The overexpression of voltage dependent anion channels (VDACs), particularly VDAC1, in cancer cells compared to normal cells, plays a crucial role in cancer cell metabolism, apoptosis regulation, and energy homeostasis. In this study, we used molecular dynamics (MD) simulations to investigate the effect of a low level of VDAC1 oxidation (induced e.g., by cold atmospheric plasma (CAP)) on the pyruvate (Pyr) uptake by VDAC1. Inhibiting Pyr uptake through VDAC1 can suppress cancer cell proliferation. Our primary target was to study the translocation of Pyr across the native and oxidized forms of hVDAC1, the human VDAC1. Specifically, we employed MD simulations to analyze the hVDAC1 structure by modifying certain cysteine residues to cysteic acids and methionine residues to methionine sulfoxides, which allowed us to investigate the effect of oxidation. Our results showed that the free energy barrier for Pyr translocation through the native and oxidized channel was approximately 4.3 ± 0.7 kJ mol-1 and 10.8 ± 1.8 kJ mol-1, respectively. An increase in barrier results in a decrease in rate of Pyr permeation through the oxidized channel. Thus, our results indicate that low levels of CAP oxidation reduce Pyr translocation, resulting in decreased cancer cell proliferation. Therefore, low levels of oxidation are likely sufficient to treat cancer cells given the inhibition of Pyr uptake.
摘要：
电压依赖性阴离子通道（VDAC）的过表达，特别是VDAC1，与正常细胞相比，在癌细胞中，在癌细胞代谢中起着至关重要的作用，凋亡调节，和能量稳态。在这项研究中,我们使用分子动力学(MD)模拟来研究低水平VDAC1氧化的影响(例如，通过冷大气等离子体（CAP））对VDAC1的丙酮酸（Pyr）吸收。通过VDAC1抑制Pyr摄取可以抑制癌细胞增殖。我们的主要目标是研究Pyr在hVDAC1的天然和氧化形式(人VDAC1)中的易位。具体来说,我们采用MD模拟来分析hVDAC1结构，通过将某些半胱氨酸残基修饰为半胱氨酸和蛋氨酸残基修饰为蛋氨酸亚砜，这使我们能够研究氧化的影响。我们的结果表明，Pyr通过天然通道和氧化通道易位的自由能势垒分别约为4.3±0.7kJmol-1和10.8±1.8kJmol-1。屏障的增加导致通过氧化通道的Pyr渗透速率降低。因此，我们的结果表明，低水平的CAP氧化会减少Pyr易位，导致癌细胞增殖减少。因此,考虑到Pyr摄取的抑制，低水平的氧化可能足以治疗癌细胞。
